帕博利珠单抗联合或不联合奥拉帕利维持治疗一线帕博利珠单抗联合化疗有效后的转移性鳞状非小细胞肺癌
Pembrolizumab With or Without Maintenance Olaparib for Metastatic Squamous NSCLC That Responded to First-Line Pembrolizumab Plus Chemotherapy.
作者信息
Hochmair Maximilian, Schenker Michael, Cobo Dols Manuel, Kim Tae Min, Ozyilkan Ozgur, Smagina Maria, Leonova Viktoriya, Kato Terufumi, Fedenko Alexander, De Angelis Flavia, Rittmeyer Achim, Gray Jhanelle E, Greystoke Alastair, Aggarwal Himani, Huang Qinlei, Zhao Bin, Lara-Guerra Humberto, Nadal Ernest
机构信息
Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria.
Sf Nectarie Oncology Center Craiova and the University of Medicine and Pharmacy of Craiova, Craiova, Romania.
出版信息
J Thorac Oncol. 2025 Feb;20(2):203-218. doi: 10.1016/j.jtho.2024.10.012. Epub 2024 Oct 28.
INTRODUCTION
Poly (adenosine diphosphate-ribose) polymerase inhibitors can up-regulate programmed cell death-ligand 1 expression and promote immune-mediated responses and may improve efficacy of first-line anti‒programmed cell death protein 1‒based therapies in patients with metastatic squamous NSCLC.
METHODS
In this randomized, double-blind, phase 3 trial (NCT03976362), adults with previously untreated stage IV squamous NSCLC received four cycles of induction therapy (pembrolizumab 200 mg every 3 weeks plus carboplatin and paclitaxel or nab-paclitaxel). Patients with disease control were randomized to 31 cycles of pembrolizumab 200 mg every 3 weeks plus olaparib 300 mg orally twice daily or placebo. Dual primary end points were progression-free survival (PFS) and overall survival (OS). PFS was tested at interim analysis 2 (the final PFS analysis); OS was tested at final analysis.
RESULTS
A total of 851 patients received induction treatment; 296 were randomized to pembrolizumab plus olaparib and 295 to pembrolizumab plus placebo. At interim analysis 2, with median follow-up of 27.1 months, median (95% confidence interval [CI]) PFS was 8.3 (6.7‒9.7) months in the pembrolizumab plus olaparib group and 5.4 (4.1‒5.6) months in the pembrolizumab plus placebo group (hazard ratio = 0.77, 95% CI: 0.63‒0.93, p = 0.0040 [not significant at a one-sided superiority boundary of p = 0.003]). At final analysis, with median follow-up of 33.4 months, median (95% CI) OS was 19.1 (15.9‒22.2) and 18.6 (16.0‒21.6) months, respectively (hazard ratio = 1.01, 95% CI: 0.83‒1.24, p = 0.5481). Treatment-related adverse events occurred in 76.5% and 65.1% of patients, respectively.
CONCLUSIONS
Adding olaparib to pembrolizumab as maintenance therapy for metastatic squamous NSCLC did not significantly improve PFS versus pembrolizumab plus placebo; neither PFS nor OS met the prespecified statistical significance boundary. No new safety signals were identified.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT03976362.
引言
聚（二磷酸腺苷-核糖）聚合酶抑制剂可上调程序性细胞死亡配体1的表达并促进免疫介导反应，可能会提高转移性鳞状非小细胞肺癌患者一线抗程序性细胞死亡蛋白1治疗的疗效。
方法
在这项随机、双盲、3期试验（NCT03976362）中，先前未经治疗的IV期鳞状非小细胞肺癌成年患者接受了4个周期的诱导治疗（帕博利珠单抗每3周200 mg加卡铂和紫杉醇或白蛋白结合型紫杉醇）。疾病得到控制的患者被随机分为两组，一组接受每3周一次200 mg帕博利珠单抗加每日口服两次300 mg奥拉帕利，另一组接受安慰剂。双主要终点为无进展生存期（PFS）和总生存期（OS）。PFS在中期分析2（最终PFS分析）时进行检验；OS在最终分析时进行检验。
结果
共有851例患者接受了诱导治疗；296例被随机分配至帕博利珠单抗加奥拉帕利组，295例被随机分配至帕博利珠单抗加安慰剂组。在中期分析2时，中位随访27.1个月，帕博利珠单抗加奥拉帕利组的中位（95%置信区间[CI]）PFS为8.3（6.7 - 9.7）个月，帕博利珠单抗加安慰剂组为5.4（4.1 - 5.6）个月（风险比 = 0.77，95% CI：0.63 - 0.93，p = 0.0040[在单侧优效性边界p = 0.003时无统计学意义]）。在最终分析时，中位随访33.4个月，中位（95% CI）OS分别为19.1（15.9 - 22.2）个月和18.6（16.0 - 21.6）个月（风险比 = 1.01，95% CI：0.83 - 1.24，p = 0.5481）。治疗相关不良事件分别发生在76.5%和65.1%的患者中。
结论
对于转移性鳞状非小细胞肺癌，在帕博利珠单抗基础上加用奥拉帕利作为维持治疗与帕博利珠单抗加安慰剂相比，并未显著改善PFS；PFS和OS均未达到预先设定的统计学意义边界。未发现新的安全信号。
试验注册
ClinicalTrials.gov，NCT03976362。
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